HAI Book 2025 - Flipbook - Page 148
Buckley, Rachel
20
Whole blood gene expression is associated with plasma p-tau217
levels via amyloid-PET and sex
Rachel F Buckley1, Vaibhav A Janve2, Mabel Seto4, Hannah M Klinger1, Jane A Brown1, Colin
Birkenbihl1, Gillian Coughlan1, Diana L Townsend1, Michael J Properzi1, Jane Zyski2, Ting-Chen
Wang2, Michelle Clifton2, Bernard J Hanseeuw1, Jasmeer Chhatwal1, Hyun-Sik Yang4, Robert A
Rissman3, Paul Aisen3, Madison Cuppels1, Michael Donohue3, Rema Raman3, Keith A Johnson1,
Reisa A Sperling4, Logan Dumitrescu2, Timothy J Hohman2
1
Massachusetts General Hospital, Boston, MA, US
Vanderbilt Univeristy Medical Center, Nashville, TN, US
3
University of Southern California, Los Angeles, CA, US
4
Brigham and Women’s Hospital, Boston, MA, US
2
Objective: Higher levels of plasma p-tau217 are associated with A´-PET burden and impending cognitive decline in
older adults, supporting it as an early marker of AD. Identifying genes in whole blood that are associated with ptau217 can elucidate biological pathways implicated in these earliest disease processes.
Method: We leveraged A´-PET (18F-Florbetapir), plasma p-tau217 (mass spectrometry, C2N Diagnostics), and whole
blood gene expression data including the autosome and X chromosomes (20,621 genes) from 724 participants
(72.2years (±4.6); 63% Female; 35% APOEε4; 26% A´+) from the A4 clinical trial at baseline (placebo[31%],
treatment[30%]) and the LEARN [39%] observational study. We ran a series of linear regressions predicting ptau217 (pg/mL) from gene expression alone, adjusting for age, BMI and cohort. Then interacted with APOEε4, sex,
and A´continuous. All analyses were FDR corrected.
Results: No genes were directly associated with p-tau217 levels. One novel transcript was moderated by APOEε4 to
predict p-tau217, while 1,535 genes were moderated by A´ (8% were X-linked), and 777 genes by A´*sex (4% Xlinked; see Fig.1). In gene*A´ models, 62% of significant genes were found to be protective (i.e., lower p-tau217 at
higher A´ burden). One example, RMND1 (b=-1.04(0.2), pFDR=0.0001), is involved in mitochondrial translation
(Fig.2A). From gene*A´*sex models, higher AMIGO2 expression, a novel membrane anchor of PDK1 that controls
cell survival and promotes neuronal survival, was positively associated with p-tau217 levels in women with higher A´
(b=0.49(0.1), pFDR=0.0005), but negatively in men (b=-0.44(0.1),pFDR=0.003; Fig.2B). Other notable pathways
implicated in our analyses were post-transcriptional modification, coordination of DNA damage, and regulation of
brain homeostasis.
Conclusion: Whole-blood transcriptomic associations with p-tau217 in clinically normal older adults are largely
moderated by A´-PET burden and sex in these analyses. Both protective and risk genes were identified
throughout the transcriptome, including the X chromosome, highlighting novel gene candidates for further
replication and validation.
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